Toll-like receptor 9 (TLR9) is the receptor for un-methylated CpG motifs in DNA which are highly represented in bacterial DNA. Two aspects of TLR9 biology are the subject of intense research in both academia and the pharmaceutical industry: 1) using agonists of the receptor to augment the immunogenicity of antigens in vaccine and to treat cancer and allergic diseases of the lung, and 2) blocking the receptor to treat inflammatory disorders. In humans, TLR9 expression in mononuclear blood cells and lymphoid organs is restricted to B cells, plasmacytoid dendritic cells (PDC), and activated neutrophils, while in mice its expression is much broader, including macrophages, myeloid DCs, activated T cells, and NK, in addition to PDCs and B cells. In mice, in vivo, triggering of TLR9 leads to an overwhelming production of pro-inflammatory cytokines such as IL-12, TNF-?, and IL-6, but very minimal type I IFN, which in humans is the predominant response following TLR9 engagement. These differences in cellular responses represent a significant limitation to the value of using mouse models to study TLR9 biology and to predict the therapeutic potential of targeting this receptor for treatment of human diseases. To obviate this problem, we propose to generate transgenic mice expressing functional human TLR9 with a human-like distribution. The specific goals of this proposal include: 1) to characterize huTLR9 transgenic mice, 2) to assess the impact of a human-like TLR9 distribution in well-established models of inflammation in which mTLR9 is known to play an important role, and 3) to evaluate whether a human-like TLR9 distribution affects the therapeutic outcome of TLR9-agonist-mediated antitumor response. This mouse model will be an invaluable resource to everyone studying the role of TLR9 in disease and developing drugs targeting the receptor.